Pathological conditions resulting from the accelerated or ongoing death of neurons are prevalent in today's society and include chronic diseases such as Alzheimer's disease and Parkinson's disease, acute diseases such as stroke, brain cell loss that follows myocardial infarction, and acute neuronal injury associated with spinal cord trauma and head trauma. Chronic and acute neurodegenerative diseases and acute neuronal injury as well as associated mortality and morbidity are largely untreatable. The consequences of patient disability resulting from these conditions is a high cost to society of patient care as well as a significant reduction in quality of life. Effective therapeutic approaches directed to the prevention or reduction of neuron death or damage associated with the above conditions are needed. At present, the greatest challenge in the development of therapeutic agents for treating conditions in the brain resulting from neuron loss include obtaining an efficacious drug that is relatively non-toxic, suitable for use in both females and males, and which can readily access the brain across the blood-brain barrier.
Estrogen compounds have been found to protect neurons from cell death and have utility in retarding the progression of neurodegenerative diseases such as Alzheimer's disease. (Simpkins et al. WO 95/12402, Behl et al. (1995) Biochem. Biophys. Res. Commun. 216: 473-482;: Bishop et al. (1994) Molecular and Cellular Neuroscience 5: 303-308; Simpkins et al. (1994) Neurobiology of Aging 15: s195-s197). Furthermore, Simpkins et al. WO 95/12402 has shown that alpha isomers of estrogen compounds, previously thought to be biologically inert, are effective in retarding neurodegeneration. This demonstration provided for the first time an opportunity to administer estrogen therapeutically to men without associated sex-related side effects.
The mechanisms by which estrogen compounds bring about a neuroprotective effect are unknown although these compounds have been shown to have a number of different physiological and biochemical effects on neurons. For example, estrogen has been shown to stimulate the production of neurotrophic agents that in turn stimulate neuronal growth. (REF) Estrogen compounds have also been found to inhibit NMDA-induced cell death in primary neuronal cultures (Bahl et al. Biochem. Biophys Res. Commun. (1995) 216: 973; Goodman et al. J. Neurochem (1996) 66: 1836), and further to be capable of removing oxygen free radicals and inhibiting lipid peroxidation. (Droescher et al. WO 95/13076). However, the potential effect of free radicals on neurons per se is unproven. Droeschler et al. describes a cell free `in vitro` assay systems using lipid peroxidation as an endpoint in which several estrogens as well as vitamin E were shown to have activity. Estradiol has also been reported to reduce lipid peroxidation of membranes (Niki (1987) Chem. Phys. Lipids 44: 227; Nakano et al. Biochem. Biophys. Res. Comm. (1987) 142: 919; Hall et al. J. Cer. Blood Flow Metab. (1991)11: 292. Other compounds including certain 21-amino steroids and a glucocorticosteroid have been found to act as anti-oxidants and have been examined for their use in spinal cord injury as well as head trauma, ischemia, and stroke. (Wilson et al. (1995) J. Trauma 39: 473; Levitt et al. (1994) J. Cardiovasc. Pharmacol 23: 136; Akhter et al. (1994) Stroke 25; 418).
As described above, a number of factors may be involved in neuroprotection. Therapeutic agents that are selected on the basis of a single biochemical mechanism may have limited generalized utility in treating disease or trauma in patients. For example, in order to achieve an anti-oxidant effect in vitro using estrogen, Droescher et al. used very high doses of estrogens. Such doses, even if effective on neurons in vivo, would have limited utility in treating chronic neurological conditions because of associated problems of toxicity that result from prolonged use of high dosages.
It would be beneficial to identify a class of compounds that are non-sex related and have demonstrated biological efficacy in protecting neurons from cell death, where such compounds could be used in the treatment of the chronic as well as the acute conditions caused by neurodegenerative diseases, trauma, and aging at non-toxic dosages. An understanding of the structural requirements for compositions capable of inducing neuroprotection would provide the basis for designing novel drugs that have enhanced neuroprotective properties while at the same time having reduced adverse side effects .